Oral contraceptives are the most frequently used form of medicamentous birth control today and very likely in the future as well. Such contraceptives were first introduced to the market in the early 1960s and have been continually improved through intensive research. In particular, the required dosage of the active ingredient was reduced so that today's oral contraceptives are dosed much lower. Besides less preferred pharmaceuticals with just a gestagen component as their active ingredient(mini-pills), oral contraceptives consist, as a rule, of an estrogen and a gestagen component. Hormones are given in the most various combinations and doses in the form of step or phase medicines that are taken over a period of 21 days followed by a 6-day interruption.
Such pharmaceuticals are known, for example, from the German patents DE-PS 32 29 612, DE-PS 41 04 385, U.S. Pat. No. 4,921,843, and German patent DE-PS 43 08 406.
The steroids that are used as gestagen component may be quite different in their chemical structure. Typical gestagens are steroids with a 17.beta.-ethinyl group and a 13-ethyl group such as desogestrel and 3-keto desogestrel, gestodene, levonorgestrel and norgestimate, as well as norethisterone, a 13-ethyl compound, or norethisterone acetate, and gestagens without a 17.beta.-ethinyl group but with a 13-methyl group such as progesterone, chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate, dydrogesterone, dienogest, etc. The various gestagens are mainly responsible for ovulation inhibition and proper transformation of the endometrium. When these sex hormones are no longer applied, the so-called (menstruation-like) withdrawal bleeding occurs.
The estrogen component is mainly responsible for the correct development (proliferation) of the endometrium (uterine mucosa) according to the cycle and thus for sufficient cycle control. Preferred estrogen components are the synthetic estrogen ethinyl estradiol that has been known for 40 years or mestranol, its 3-methyl ester. The latter is a prodrug that, after resorption and passage through the liver, is transformed into ethinyl estradiol, its active form. Other synthetic estrogens such as stilbene and moxestrol have not proved to be useful due to the high toxic risk they pose.
Synthetic introduction of the 17.beta.-ethinyl group prevents conversion of 17.beta.-estradiol, the parent substance, to the much less effective estrone, which guarantees a good proliferative effect on the endometrium and good cycle stability even at extremely low doses of 0.02 to 0.03 mg a day. Ethinyl estradiol or its prodrug mestranol, however, have a number of serious toxicological and pharmacological disadvantages. Thus ethinyl estradiol is resorbed badly and quite differently from person to person in the gastrointestinal tract which results in insufficient bioavailability. Furthermore, application of ethinyl estradiol significantly increases the risk of thrombosis or thromboembolism. Ethinyl estradiol also acts as a suicidal inhibitor on certain isoenzymes of the cytochrome P-450 system. This leads to an inhibition of endogenous catabolic and metabolic pathways. As gestagens and many other active ingredients are decomposed and metabolized to a major extent via these pathways as well, repeated application causes accumulation of these agents in the body. Other undesired side effects are a rise in blood pressure due to the induction of angiotensinogen or renin in the liver, and the carcinogenic capability of this substance (Bao Thing Zhu, Roy D, Liehr J: The carcinogenic activity of ethinyl estrogens is determined both by their hormonal characteristics and their conversion to catechol metabolites. Endocrinology 132:577-583, 1993).
Despite these considerable disadvantages, no alternative agents for use as oral contraceptives were found. There is still a great need for toxicologically less unsafe compounds for use as contraceptives.
One toxicologically safer compound that could be used is endogenous 17.beta.-estradiol that could be administered in micronized form or as a fatty acid ester (e.g. estradiol valerate). This non-synthetic hormone holds a number of pharmacological and toxicological advantages, for example, its hypotensive effect (Clarkson, T B: Experimental effects of estradiol versus progestins on arterial wall. Gynecol. Endocrinol. 6, Suppl. 1, 15; 1992), reversal of contraction of the vessels caused by endothelins (Jiang C, Poole-Wilson P A, Sarrel P M, Campbell S, Collins W: Effect of 17.beta.-estradiol on contraction, Ca.sup.2+ current and intracellular free Ca.sup.2+ in guinea pig isolated cardiac myocytes. Br. J. Pharmacol. 104: 739, 1992; Jiang C, Sarrel P M, Poole-Wilson P A, Collins W: Acute effect of 17.beta.-estradiol on rabbit coronary artery contractile responses to endothelin-1. Am. J. Physiol. 263: H271, 1992), inhibition of lipid peroxidation in cell membranes and of LDL cholesterol oxidation as initial steps of an atherosclerosis (Mooradian A D: Antioxidant properties of steroids. J. Steroid Biochem. 45: 509-511, 1993), deceleration of osteoclasts and thus of osteoclasis as part of an osteoporosis prevention or treatment, and alleviation of Alzheimer-type senile dementia.
These advantages of 17.beta.-estradiol have resulted in its frequent use in hormone replacement therapy (HRT) during menopause and postmenopause in women as described, for example, in German patents DE-PS 32 13 248 and DE-PS 26 45 307.
Use of this endogenous hormone together with a gestagen component as the only estrogen component of compound preparations for contraception was prevented by the occurrence of unacceptable disorders of the menstrual cycle; there was no breakthrough despite much effort on the part of researchers. The gestagen component of such compound preparations gives good and safe contraceptive protection but there is frequent intermenstrual bleeding as gestagen stimulates local enzymes that cause increased inactivation of the estradiol contained in the endometrium which sharply reduces the effect of estradiol on the endometrium. What has been described so far are compound contraceptives that contain both synthetic and biogenous estrogens. The resulting advantage is that much lower active ingredient concentrations are required (DE-PS 43 08 406). Still, use of synthetic estrogens has not yet been completely dispensed with.
As endogenous estrogens could not be used for contraception to any satisfactory extent, an acceptable "pill" for women to be used at all stages of life, i.e. for contraception in their fertile period and, at the same time, for hormone replacement after biosynthesis of estradiol in their ovaries has ceased, that is, during menopause and postmenopause, has not been developed.
Another disadvantage of known compound or sequential preparations used for contraception is the relatively long break between the 21- to 27-day intake periods during which there is a withdrawal bleeding that simulates natural menstrual bleeding (see, for example, DE-PS 32 29 612). For example, an ovulation-inhibiting pharmaceutical is known from U.S. Pat. No. 4,921,843 that is administered as follows: after having taken the last daily doses of the second hormonal component there is a break of at least one day, preferably two days, that could be bridged by a placebo before a new daily hormone dose of the first hormonal component of the next cycle is taken. This corresponds with the opinion that prevails among experts that such an intake break of at least one day, or a significant reduction of the effective estrogen level, is a condition for triggering the withdrawal bleeding. But if estrogen is not taken, even for only one day, there may be changes in blood flow that give rise to headache (e.g. migrainous attacks). In addition, there may be short-term alterations of other metabolic parameters, for example, of hemostasis. The compound preparation described in DE-PS 41 04 385 is meant for uninterrupted administration of the estrogen component over the whole menstrual cycle but the pharmaceutical proposed there fails to overcome the difficulties that occur when biogenous estrogens are used. So there are still risks in connection with the use of endogenous estrogens in compound preparations designed for contraception.
The problem to be solved by the present invention is to develop further an ovulation-inhibiting agent of the identified kind so that it combines high contraceptive safety with perfect cycle control while positively preventing intermenstrual bleeding and side effects.
Another problem of the invention is to provide such an agent that permits the use of endogenous estrogens.
It is yet another problem of the invention to provide an agent that can be used in women both for contraception and for hormone replacement during menopause and postmenopause.